It is becoming increasingly apparent that N0, a short-lived reactive nitrogen intermediate produced by a variety of cell types, plays a critical role in diverse physiological processes including regulation of blood pressure, neurotransmission, respiration, gastric motility, renal function, wound healing, cell growth, and cytotoxicity. Recent studies have also implicated N0 in the pathogenesis of tissue injury. The overall objective of this program project is to examine the role of N0 oxide in the pathophysiology of chemical induced tissue injury. The overall hypothesis that provides a basis for the proposed research of the program project is that N0 is produced in tissues in excess quantities following exposure to toxic chemicals and N0 or its oxidation products can act directly on the tissue to promote injury. As an alternative to the latter hypothesis, it is postulated that N0 may protect the tissue from injury by scavenging reactive oxygen intermediates. Thus, the role of N0 in toxicity may depend on the specific toxicant, the target tissue and the extent to which reactive oxygen intermediates are involved in tissue injury. The program project consists of five projects aimed at addressing various aspects of this hypothesis. These include: Pharmacologic Regulation of Nitric Oxide; Novel Mechanisms Regulating Nitric Oxide in the Skin; Astrocytic Oxide an Glial Function; Regulation of Nitric Oxide Synthesis and Toxicity by Osteopontin; and, Role of Nitric Oxide in Tetrachlorodibenzo-p-dioxin (TCCD)-Mediated Toxicity. A strong chemistry support laboratory has been organized and is integral to each project for expertise in analytical chemistry and for the development and production of novel inhibitors of N0 synthetase that will be used by the program's research groups. The key to the successful of this program project will be to integrate the knowledge gained in these studies into a cohesive model to explain the contribution of nitric oxide to chemical-induced toxicity.